Although the incidence of gastric ulceration, duodenal ulceration or gastritis has been declining over the last decade, about 10% of the population will develop this condition at some time during their lives. The precise cause of these diseases remains uncertain despite of intensive clinical and laboratory research, but it is explained that they are induced from imbalance in equlibrium between potentially damaging factor present in the lumen of the stomach or duodenum and the process which enable these tissues to resist autodigestion.
The first line therapy for gastritis and gastric ulcer is to promote the effects of treatments by attenuating the attacking factors by administering antisecretory agents such as antacid, H2 antagonists and proton pump inhibitors. However, it has been reported that in the cases of omeprazole or long acting H2 antagonists, the duration of action was so long more than 24 hours that their long-term administration to rats caused dysplasia in epidermal cells of mucous membrane in gastrointestinal tracts (Ekman, L. et al., Scand. J. Gastroentrol.1985, 20 suppl.108: 53). And long-term administration of antisecretory agents is frequently associated with formation of gastric tumors in animals (Garner, A., Advances in Drug Therapy of Gastrointestinal Ulceration; Garner, A. and Whittle, B. J. R.(Eds.), Wiley & Sons, 1989, 275-88). Furthermore, a majority of patients with peptic ulcer disease have acid outputs within the normal range (Baron, J. H., Clinical Tests of Gastric Secretion. Macmillan, London, 1978, 86-119), so the treatments with antisecretory agents are not fundamental therapy and have a little effect on the prevention of recurrence, though they enhance acute healing of ulcer.
On the contrary cytoprotective agents such as sucralfate showed low frequency of recurrence (Marks, I. N., et al., Scand. J. Gastroentrol. 1983, 18 Suppl.83: 53. Shorrock, C. J., et al., Gut 1990, 31: 26), which implies that stimulating of mucosal defence is more desirable than attenuating the attacking factors for treatment of these diseases.
The anti-ulcer action without antisecretory activity is referred to as `cytoprotection`. This cytoprotection is known to be due to the function of prostaglandins released from the gastric mucous membrane (Robert, A., 1981. Gastroenterology,16 Suppl.67: 223). Various kinds of prostaglandins such as PEI.sub.2, PGE.sub.2 are mainly generated in the gastric mucosa, and they effectively prevent the experimental ulceration induced by various kinds of ulcerogens (Robert. A., 1976. Advances in Prostaglandin and Thromboxane Research, Raven Press, New York, Vol 2, p.507). It was clinically proved that misoprostol, one of the prostaglandin compounds, prevented the gastric ulcer induced by NSAIDs (Graham, D. Y., et al., Lancet 1988, 2: 1277; Edelson, J. T., et al., JAMA 1990, 264: 41).
The cytoprotective mechanism of prostaglandins includes stimulating the blood flow of gastric mucosa (Guth, P. H., et al., Gastroenterology, 1984, 87: 1083), promoting mucus secretion (Allen, A., et al., Gut 1980, 21: 249; Rees, W. D. W., et al., Clin. Sci. 1982, 62: 343), promoting the gastric alkali secretion (Dayton, M. T., et al., Dig. Dis. Sci. 1983, 28; 449; Miller, T. A., et al., ibid 1983, 28; 641), preventing against the destruction of the gastric mucous defenses (Cheung, L. Y., Prostaglandins 1981, 21: 125), promoting the active transportation of sodium (Chaudhury, T. K., et al., Dig. Dis. Sci. 1980, 25: 830), stabilizing the lysozymes (Ferguson, W. W., et al., Am. Surg. 1973, 177: 648), and so on.
It has been also suggested that the tissue damages of many organs are induced by reactive oxygen species, such as lipid peroxides (Fridrich J., Science, 1978, 201: 875; Halliwell B, et al., Lancet 1984, 1: 1396; Freeman B A, et al., Lab Invest, 1982, 47: 412). And it was demonstrated that free radical scavengers have effects on protecting mucosa from damages induced by ischemic reperfusion (Peery, M. A., et al., Gastroentero logy, 1986, 90: 362), and then two enzymic antioxidants SOD and catalase could significantly reduce the extent of gastric mucosal damage induced by NSAIDs (Pihan, G., et al., Dig Dis Sci, 1987, 32:1395). It has been known that NSAIDs such as indomethacin induce adherence of leukocytes to the vascular endothelium and activation of neutrophils is accompanied by release of the active oxygens which can damage the gastrointestinal tracts (Klebanoff, S. J., Inflammation: Basic Principles and Clinical Correlates, New York: Raven, 1988, p.391-444; Vaananen P. M, et al., Am. J. Physiol., 1991, 256: G470-G475).
Particularly, it has been known that the active oxygens play an important role in the mucosal damage of inflammatory bowel disease (Simmonds N. J, et al., Gastroenterology, 1992, 103: 186), duodenal ulcer(Salim A. S, Dig. Dis. Sci., 1989, 35: 73), and Helicobacter pylori-induced gastric ulcer (Mooney C., et al., Gut, 1991, 32: 853).
Inflammatory bowel diseases, which are idiopathic chronic and refractory diseases having high relapsy, include ulcerative colitis and Crohn's disease. Though pathophysiology of the inflammatory bowel diseases remains unclear, inflammatory mediators such as leukotrienes is known to induce sustaining inflammation on the mucous membrane (Rachmilewitz, D., et al., Gastroenterology, 1989, 97: 326) as well as reactive oxygen species (Keshavarzian A., et al., Gastroenterology, 1992, 103: 177). Actually leukotriene inhibitors (Wallace J. L., et al., Gastroenterology, 1989, 96: 29; Zingarelli B, et al., Agents Actions 1993, 39: 150) reduced the damage of inflamed colon effectively.
On the other hand, flavonoid compounds which exist in nature show various effects, for example natural flavonoids such as hypolaetin-8-glucoside, apigenin-7,4'-dimethylether, kampferol, quercetin, naringenin, and hesperidine are known to have anti-ulcerative action (J.Pharm. Pharmacol.1984, 36: 820; Ind. J. Pharm. Sci. 1981, 43: 159; Ind. J. Exp. Biol. 1988, 26: 121; Phytotherapy Res.1992, 6: 168; ibid, 1988, 2: 137).
It has also been reported by Ares et al.(1995) that synthetic flavone derivatives such as 4'-fluoro-5-methoxy flavone, provide protective effect on the damage of gastric mucosa (U.S. Pat. No. 5,399,584).
We, the inventors of the present invention have synthesized many flavonoid compounds and screened, since small change of chemical structure of flavonoids can lead to different biological effects. And we have discovered that the appropriately substituted flavone/flavanone compounds in the formula(I) and their salts have better function of cytoprotection on gastrointestinal tracts including large intestine, than known compounds of flavone/flavanone.